WO2019142128A1 - Inhibiteurs doubles de l'alk5 et de la map kinase p38α - Google Patents

Inhibiteurs doubles de l'alk5 et de la map kinase p38α Download PDF

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Publication number
WO2019142128A1
WO2019142128A1 PCT/IB2019/050391 IB2019050391W WO2019142128A1 WO 2019142128 A1 WO2019142128 A1 WO 2019142128A1 IB 2019050391 W IB2019050391 W IB 2019050391W WO 2019142128 A1 WO2019142128 A1 WO 2019142128A1
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Prior art keywords
pyridin
pyrrolo
fluorophenyl
nhr
optionally substituted
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PCT/IB2019/050391
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English (en)
Inventor
Sarvajit Chakravarty
Dhananjay PENDHARKAR
Dilip V JARIKOTE
Bhausaheb B BHAGWAT
Anil K Agarwal
Brahmam PUJALA
Sreekanth A Ramachandran
Sagar PATNI
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Integral Biosciences Private Limited
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Priority to US16/632,213 priority Critical patent/US20200171030A1/en
Publication of WO2019142128A1 publication Critical patent/WO2019142128A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present disclosure generally relates to the compounds that exhibits protein kinase inhibitory activity. Specifically, the present disclosure provides compounds of Formula (IA) that exhibits dual inhibitory activity against ALK5 and P38 ⁇ MAP kinase. The present disclosure also provides process(es) for preparation of such compounds, pharmaceutical compositions containing one or a combination of these compounds, and methods of treatment of conditions associated with excessive activity of any or a combination of transforming growth factor-beta (TGF ⁇ ) and p38 mitogen-activated protein kinase (MAPK) utilizing these compounds.
  • TGF ⁇ transforming growth factor-beta
  • MAPK mitogen-activated protein kinase
  • TGF ⁇ belongs to a superfamily of multifunctional proteins that include, for example, TGF ⁇ l, TGF ⁇ 2, and TGF ⁇ 3, which are pleiotropic modulators of cell growth and differentiation, embryonic and bone development, extracellular matrix formation, hematopoiesis, and immune and inflammatory responses.
  • TGF ⁇ l inhibits the growth of many cell types, including epithelial cells, but stimulates the proliferation of various types of mesenchymal cells.
  • Other members of this superfamily include activin, inhibin, bone morphogenic protein, and Mullerian inhibiting substance.
  • the members of the TGF ⁇ family initiate intracellular signaling pathways leading ultimately to the expression of genes that regulate the cell cycle, control proliferative responses, or relate to extracellular matrix proteins that mediate outside-in cell signaling, cell adhesion, migration and intercellular communication.
  • Fibroproliferative diseases include kidney disorders associated with unregulated TGF ⁇ activity and excessive fibrosis including glomerulonephritis (GN), such as mesangial proliferative GN, immune GN, and crescentic GN.
  • GN glomerulonephritis
  • Other renal conditions include diabetic nephropathy, renal interstitial fibrosis, renal fibrosis in transplant patients receiving cyclosporine, and HIV -associated nephropathy.
  • Collagen vascular disorders include progressive systemic sclerosis, polymyositis, scleroderma, dermatomyositis, eosinophilic fasciitis, morphea, or those associated with the occurrence of Raynaud's syndrome.
  • Lung fibroses resulting from excessive TGF ⁇ activity include adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, and interstitial pulmonary fibrosis often associated with autoimmune disorders, such as systemic lupus erythematosus and scleroderma, chemical contact, or allergies.
  • Another autoimmune disorder associated with fibroproliferative characteristics is rheumatoid arthritis. Fibroproliferative conditions can be associated with surgical eye procedures. Such procedures include retinal reattachment surgery accompanying proliferative vitreoretinopathy, cataract extraction with intraocular lens implantation, and post glaucoma drainage surgery.
  • TGF- ⁇ Transforming growth factor- ⁇
  • TGF- ⁇ a family of cytokines regulates a plethora of cellular processes, including growth control, differentiation, extracellular matrix production, migration, survival, apoptosis and immune suppression. This in part due to their ability to exert direct control over multiple signaling networks in addition to the control of the canonical SMAD-dependent signaling pathway.
  • Some of the SMAD-independent pathways which are influenced by TGF- ⁇ ligands include the mitogen-activated protein kinase (MAPK) pathways, the PI3K/AKT/mTOR pathways and the RhoA-dependent signaling pathways.
  • MAPK mitogen-activated protein kinase
  • p38 mitogen activated protein kinase (p38MAPK) pathway has been shown to contribute in TGF- ⁇ -mediated EMT and tumor cell migration. It has also been shown that co-administration of a P38 ⁇ inhibitor and an ALK5 inhibitor modulated the development of fibrosis in Adriyamicin induced renal fibrosis model via the reduction in active TGF-1 production, reduced myofibroblast accumulation, and decreased expression of collagen type IV and fibronectin. Even though 4 isoforms of P38 MAPK are known, most stimuli result in the activation of P38 ⁇ by the MAP kinase kinases (MKKs).
  • MKKs MAP kinase kinases
  • p38 mitogen-activated protein kinase (MAPK) pathway and transforming growth factor TGF ⁇ 1/Smad signaling pathway are thus important intracellular signaling pathways involved in many human diseases such as inflammation and cancer.
  • ALK5 and p38 inhibitors The synergistic value of inhibiting these two pathways has been explored using combination of ALK5 and p38 inhibitors.
  • Primary object of the present disclosure is to provide dual ALK5/P38 ⁇ kinase inhibitor compounds.
  • Another object of the present disclosure is to provide a method of synthesis of compounds that possess dual ALK5/P38 ⁇ kinase inhibitory activity.
  • Another object of the present disclosure is to provide method of treatment of conditions associated with excessive activity of any or a combination of ALK5 and P38 ⁇ kinase.
  • Another object of the present disclosure is to provide method of treatment of cancer by administering at least one agent that inhibit any or a combination of ALK5 and P38 ⁇ MAP kinase.
  • Another object of the present disclosure is to provide method of treatment of inflammatory disease/ailment by administering at least one agent that inhibit any or a combination of ALK5 and P38 ⁇ MAP kinase.
  • Another object of the present disclosure is to provide method of treatment of cancer by administering at least one agent that inhibit any or a combination of ALK5 and P38 ⁇ MAP kinase in combination with at least one immunotherapeutic agent.
  • Another object of the present disclosure is to provide method of treatment of inflammatory disease by administering at least one agent that inhibit any or a combination of ALK5 and P38 ⁇ MAP kinase in combination with at least one anti-inflammatory agent.
  • Still another object of the present disclosure is to provide pharmaceutical compositions containing at least one compound that inhibit ALK5 and P38 ⁇ MAP kinase.
  • Still further object of the present disclosure is to provide pharmaceutical compositions containing at least one compound possessing dual inhibitory activity against ALK5 and P38 ⁇ MAP kinase that find utility in treatment of cancer.
  • Still further object of the present disclosure is to provide pharmaceutical compositions containing at least one compound possessing dual inhibitory activity against ALK5 and P38 ⁇ MAP kinase that find utility in treatment of inflammatory disease.
  • the present disclosure generally relates to the compounds that exhibits protein kinase inhibitory activity. Specifically, the present disclosure provides compounds of formula (I) that exhibits dual inhibitory activity against ALK5 and P38 ⁇ MAP kinase. The present disclosure also provides process(es) for preparation of such compounds, pharmaceutical compositions containing one or a combination of these compounds, and methods of treatment of conditions associated with excessive activity of any or a combination of transforming growth factor-beta (TGF ⁇ ) and p38 mitogen-activated protein kinase (MAPK) utilizing these compounds.
  • TGF ⁇ transforming growth factor-beta
  • MAPK mitogen-activated protein kinase
  • An aspect of the present disclosure provides a compound of Formula (IA) and pharmaceutically acceptable salt, polymorph, solvate or stereoisomer thereof:
  • L represents -C(O)C(O)-;
  • X and Y independently represent CR 1 or N;
  • A represents any of: (i) H, -NH 2 , -NHR 1 , -NR 1 R 2 , N + (O-)R 1 R 2 , -NHC(O)H, - NHC(O)R 1 , -NR 1 C(O)R 1 , -NHC(O)NH 2 , -NHC(O)NR 1 R 2 , - NR 1 C(O)NHR 1 , -SR 1 , - SO 2 NR 1 R 1 , -C(O)NH 2 , -C(O)NHR 1 , -C(O)NR 1 R 2 , -CONHSO 2 H, -C(O)NHSO 2 R 1 , - C(O)NR 1 SO 2 R 1 ; or (ii) cyclic C 3 -C 7 alkylamino, imidazolyl
  • Z represents an optionally substituted aryl or an optionally substituted heteroaryl having up to 12 carbon atoms with one or more heteroatoms selected from O, N and S;
  • B represents H, halogen, C 1-6 linear or branched alkyl, acyl, C 3-8 cycloalkyl, C 1- C 4 haloalkyl, C 1- C 4 haloalkoxy, CHR 2a R 2b, -OH, -OR 1 , and -OCR 2a , wherein R 2a andR 2b independently represent H, C 1-6 linear or branched alkyl, C 3-8 cycloalkyl, optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms with one or more heteroatoms selected from O, N and S, optionally said aryl group and hetroaryl group are substituted with R 4 ; R 4 represents any of
  • the compound of Formula (IA) exhibits dual inhibitory activity against ALK5 and P38 ⁇ MAP kinase.
  • the compound is of any of Formula (IIA), Formula (III) or Formula (IV):
  • L represents -C(O)C(O)-;
  • A represents any of: (i) H, -NH 2 , -NHR 1 , -NR 1 R 2 , N + (O-)R 1 R 2 , -NHC(O)H, - NHC(O)R 1 , -NR 1 C(O)R 1 , -NHC(O)NH 2 , -NHC(O)NR 1 R 2 , - NR 1 C(O)NHR 1 , -SR 1 , - SO 2 NR 1 R 1 , -C(O)NH 2 , -C(O)NHR 1 , -C(O)NR 1 R 2 , -CONHSO 2 H, -C(O)NHSO 2 R 1 , - C(O)NR 1 SO 2 R 1 ; or (ii) cyclic C3-C7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thio
  • X and Y represent CR 1 ;
  • Z represents an optionally substituted aryl or an optionally substituted heteroaryl having up to 12 carbon atoms with one or more heteroatoms selected from O, N and S;
  • B represents H, halogen, C 1-6 linear or branched alkyl, acyl, C 3-8 cycloalkyl, C 1-C4 halo alkyl, C 1- C 4 halo alkoxy, CHR 2a R 2b, -OH, -OR 1 , and -OCR 2a , wherein R 2a andR 2b independently represent H, C 1 -C 6 linear or branched alkyl, C 3-8 cycloalkyl, optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms with one or more heteroatoms selected from O, N and S, optionally said aryl group and hetroaryl
  • R 4a and R 4b independently represent H, C 1 -C 6 linear or branched alkyl, C 3-8 cycloalkyl, Halo, OH, NH 2 , and– CONH 2 ; n is 0 or an integer from 1-2; and m is 0 or 1,
  • the compound is of any of Formula (IIB) or Formula (IVA) or Formula (IVB):
  • Formula (IIB) Formula (IVA) Formula (IVB) wherein: A represents any of: (i) H, -NH 2 , -NHR 1 , -NR 1 R 2 , N + (O-)R 1 R 2 , -NHC(O)H, - NHC(O)R 1 , -NR 1 C(O)R 1 , -NHC(O)NH 2 , -NHC(O)NR 1 R 2 , - NR 1 C(O)NHR 1 , -SR 1 , - SO 2 NR 1 R 1 , -C(O)NH 2 , -C(O)NHR 1 , -C(O)NR 1 R 2 , -CONHSO 2 H, -C(O)NHSO 2 R 1 , - C(O)NR 1 SO 2 R 1 ; or (ii) cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morpholinyl
  • R 4 represents any of C 1-6 linear or branched alkyl, acyl, halogen, C 3-8 cycloalkyl, C 1 -C 4 halo alkyl, C 1 -C 4 halo alkoxy, CHR 2a R 2b, -OH, -OR 1 , and -OCR 2a , wherein R 2a andR 2b independently represent H, C 1 -C 6 linear or branched alkyl, C 3-8 cycloalkyl, optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms with one or more heteroatoms selected from O, N and S, optionally said aryl group and hetroaryl group are substituted with R 4 ; R 4 represents any of C 1-6 linear or branched alkyl, acyl, halogen, C 3-8 cycloalkyl, C 1 -C
  • R 4a and R 4b independently represent H, C 1 -C 6 linear or branched alkyl, C 3-8 cycloalkyl, Halo, OH, NH 2 , and– CONH 2 ;
  • n is 0 or an integer from 1-5.
  • the compound is of Formula (V) and pharmaceutically acceptable salt, polymorph, solvate or stereoisomer thereof:
  • R 1 and R 2 is independently H, halogen, -OH, -OR 1 , -OCR 1 –CONR 1 , OC(O)R 1 , - OC(O)NH 2 , OC(O)NHR 1 , -OC(O)NR 1 R 2 , -NO 2 , -NH 2 , -NHR 1 , -NR 1 R 2 , N + (O-)R 1 R 2 , - NHC(O)H, -NHC(O)R 1 , -NR 1 C(O)R 1 , -NHC(O)NH 2 , -NHC(O)NR 1 R 2 , - NR 1 C(O)NHR 1 , -SH, -SR 1 , -S(O)H, -S(O)R 1 , -SO 2 R 1 , -SO2NH 2 , -SO 2 NHR 1 , - SO 2 NR 1 R 2 , CF
  • said compound or a pharmaceutically acceptable salt, polymorph, solvate or stereoisomer thereof being used for manufacture of a medicament for treatment of a disorder characterized by excessive level of any or a combination of ALK5 and P38 ⁇ MAP kinase.
  • composition “composition”“blend,” or“mixture” are all intended to be used interchangeably.
  • weight percent refers to the concentration of a substance as the weight of that substance divided by the total weight of the composition and multiplied by 100. It is understood that, as used here,“percent,” and the like are intended to be synonymous with“weight percent,”“wt-%,” etc.
  • the present disclosure generally relates to the compounds that exhibits protein kinase inhibitory activity. Specifically, the present disclosure provides compounds of formula (1) that exhibits dual inhibitory activity against ALK5 and P38 ⁇ MAP kinase. The present disclosure also provides process(es) for preparation of such compounds, pharmaceutical compositions containing one or a combination of these compounds, and methods of treatment of conditions associated with excessive activity of any or a combination of transforming growth factor-beta (TGF ⁇ ) and p38 mitogen-activated protein kinase (MAPK) utilizing these compounds.
  • TGF ⁇ transforming growth factor-beta
  • MAPK mitogen-activated protein kinase
  • L is -C(O)C(O)-;
  • X and Y independently represent CR 1 or N;
  • A represents any of: (i) H, -NH 2 , -NHR 1 , -NR 1 R 2 , N + (O-)R 1 R 2 , -NHC(O)H, - NHC(O)R 1 , -NR 1 C(O)R 1 , -NHC(O)NH2, -NHC(O)NR 1 R 2 , - NR1C(O)NHR 1 , -SR1, - SO2NR 1 R 1 , -C(0)NH 2 , -C(0)NHR 1 , -C(O)NR 1 R 2 , -CONHS0 2 H, -C(O)NHSO 2 R 1 , - C(O)NR 1 SO 2 R 1 , or (ii) cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morph
  • the compounds of Formula (I) exhibits dual inhibitory activity against ALK5 and P38 ⁇ MAP kinase.
  • An aspect of the present disclosure provides a compound of Formula (IA) and pharmaceutically acceptable salt, polymorph, solvate or stereoisomer thereof:
  • L represents -C(O)C(O)-;
  • X and Y independently represent CR 1 or N;
  • A represents any of: (i) H, -NH 2 , -NHR 1 , -NR 1 R 2 , N + (O-)R 1 R 2 , -NHC(O)H, - NHC(O)R 1 , -NR 1 C(O)R 1 , -NHC(O)NH 2 , -NHC(O)NR 1 R 2 , - NR 1 C(O)NHR 1 , -SR 1 , - SO 2 NR 1 R 1 , -C(O)NH 2 , -C(O)NHR 1 , -C(O)NR 1 R 2 , -CONHSO 2 H, -C(O)NHSO 2 R 1 , - C(O)NR 1 SO 2 R 1 ; or (ii) cyclic C 3 -C 7 alkylamino, imidazolyl
  • Z represents an optionally substituted aryl or an optionally substituted heteroaryl having up to 12 carbon atoms with one or more heteroatoms selected from O, N and S;
  • B represents H, halogen, C 1-6 linear or branched alkyl, acyl, C 3-8 cycloalkyl, C 1 -C 4 halo alkyl, C 1 -C 4 halo alkoxy, CHR 2a R 2b, -OH, -OR 1 , and -OCR 2a , wherein R 2a andR 2b independently represent H, C 1 -C 6 linear or branched alkyl, C 3-8 cycloalkyl, optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms with one or more heteroatoms selected from O, N and S, optionally said aryl group and hetroaryl group are substituted with R 4
  • R 4a and R 4b independently represent H, C 1 -C 6 linear or branched alkyl, C 3-8 cycloalkyl, Halo, OH, NH 2 , and– CONH 2 ;
  • n is 0 or an integer from 1-2; and m is 0 or 1,
  • the present disclosure provides a dual ALK5 and P38 ⁇ MAP kinase inhibitor compound of Formula (II) and pharmaceutically acceptable salt, polymorph, solvate or stereoisomer thereof:
  • L is -C(O)C(O)-;
  • A represents any of: (i) H, -NH 2 , -NHR 1 , -NR 1 R 2 , N+(O-)R 1 R 2 , -NHC(O)H, - NHC(O)R 1 , -NR 1 C(O)R 1 , -NHC(O)NH 2 , -NHC(O)NR 1 R 2 , - NR1C(O)NHR 1 , -SR 1 , - SO2NR 1 R 1 , -C(O)NH 2 , -C(O)NHR 1 , -C(O)NR 1 R 2 , -CONHSO 2 H, -C(O)NHSO 2 R 1 , - C(O)NR 1 SO 2 R 1 , or (ii) cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thio
  • A represents any of -NHR 1 , -NR 1 R 2,
  • A represents any of -NHR 1 , -NR 1 R 2,
  • the compound is of any of Formula (IIA), Formula (III) or Formula (IV):
  • L represents -C(O)C(O)-;
  • A represents any of: (i) H, -NH 2 , -NHR 1 , -NR 1 R 2 , N + (O-)R 1 R 2 , -NHC(O)H, - NHC(O)R 1 , -NR 1 C(O)R 1 , -NHC(O)NH 2 , -NHC(O)NR 1 R 2 , - NR 1 C(O)NHR 1 , -SR 1 , - SO 2 NR 1 R 1 , -C(O)NH 2 , -C(O)NHR 1 , -C(O)NR 1 R 2 , -CONHSO 2 H, -C(O)NHSO 2 R 1 , - C(O)NR 1 SO 2 R 1 ; or (ii) cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morpholinyl, thi
  • X and Y represent CR 1 ;
  • Z represents an optionally substituted aryl or an optionally substituted heteroaryl having up to 12 carbon atoms with one or more heteroatoms selected from O, N and S;
  • B represents H, halogen, C 1-6 linear or branched alkyl, acyl, C 3-8 cycloalkyl, C 1 -C 4 halo alkyl, C 1 -C 4 halo alkoxy, CHR 2a R 2b, -OH, -OR 1 , and -OCR 2a , wherein R 2a andR 2b independently represent H, C 1 -C 6 linear or branched alkyl, C 3-8 cycloalkyl, optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms with one or more heteroatoms selected from O, N and S, optionally said aryl group and
  • R 4a and R 4b independently represent H, C 1 -C 6 linear or branched alkyl, C3-8 cycloalkyl, Halo, OH, NH 2 , and– n is 0 or an integer from 1-2; and m is 0 or 1,
  • the compound is of any of Formula (IIB) or Formula (IVA) or Formula (IVB):
  • Formula (IIB) Formula (IVA) Formula (IVB) wherein: A represents any of: (i) H, -NH 2 , -NHR 1 , -NR 1 R 2 , N + (O-)R1R2, -NHC(O)H, - NHC(O)R 1 , -NR 1 C(O)R 1 , -NHC(O)NH 2 , -NHC(O)NR 1 R 2 , - NR 1 C(O)NHR 1 , -SR 1 , - SO 2 NR 1 R 1 , -C(O)NH 2 , -C(O)NHR 1 , -C(O)NR 1 R 2 , -CONHSO 2 H, -C(O)NHSO 2 R 1 , - C(O)NR 1 SO 2 R 1 ; or (ii) cyclic C 3 -C 7 alkylamino, imidazolyl, piperazinyl, morpholinyl,
  • R 4 represents any of C 1-6 linear or branched alkyl, acyl, halogen, C 3-8 cycloalkyl, C 1 -C 4 halo alkyl, C 1 -C 4 halo alkoxy, CHR 2a R 2b, -OH, -OR 1 , and -OCR 2a , wherein R 2a andR 2b independently represent H, C 1 -C 6 linear or branched alkyl, C 3-8 cycloalkyl, optionally substituted aryl, and an optionally substituted heteroaryl group having up to 12 carbon atoms with one or more heteroatoms selected from O, N and S, optionally said aryl group and hetroaryl group are substituted with R 4 ; R 4 represents any of C 1-6 linear or branched alkyl, acyl, halogen, C 3-8 cycloalkyl, C 1 -C
  • the present disclosure provides a dual ALK5 and P38 ⁇ MAP kinase inhibitor compound of Formula (V) and pharmaceutically acceptable salt, polymorph, solvate or stereoisomer thereof:
  • R 1 and R 2 is independently H, halogen, -OH, -OR 1 , -OCR 1 –CONR 1 , OC(O)R 1 , - OC(O)NH 2 , OC(O)NHR 1 , -OC(O)NR 1 R 2 , -NO 2 , -NH 2 , -NHR 1 , -NR 1 R 2 , N + (O-)R 1 R 2 , - NHC(O)H, -NHC(O)R 1 , -NR 1 C(O)R 1 , -NHC(O)NH 2 , -NHC(O)NR 1 R 2 , - NR 1 C(O)NHR 1 , -SH, -SR 1 , -S(O)H, -S(O)R 1 , -SO 2 R 1 , -SO2NH 2 , -SO 2 NHR 1 , - SO 2 NR 1 R 2 , CF
  • the present disclosure provides use of a compound of Formula (I), Formula (IA), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (IVA), Formula (IVB) or Formula (V), or a pharmaceutically acceptable salt, polymorph, solvate or stereoisomer thereof, for manufacture of a medicament for treatment of a disorder characterized by excessive level of any or a combination of ALK5 and P38 ⁇ MAP kinase.
  • the present disclosure provides a pharmaceutical composition including a compound of Formula (I), Formula (IA), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (IVA), Formula (IVB) or Formula (V), as defined above, or a pharmaceutically acceptable salt, polymorph, solvate or stereoisomer thereof, in combination with one or more pharmaceutically acceptable carrier(s), diluent(s) and/or excipient(s).
  • a "pharmaceutically acceptable carrier, diluent, or excipient” is a medium generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans.
  • Such carriers are generally formulated according to a number of factors well within the purview of those of ordinary skilled in the art to determine and account for. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted.
  • Pharmaceutically acceptable carriers and excipients include both aqueous and nonaqueous liquid media, as well as a variety of solid and semi- solid dosage forms.
  • Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources, e.g., Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985.
  • the compounds of Formula (I), Formula (IA), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (IVA), Formula (IVB) or Formula (V), may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • the pharmaceutical compositions containing compounds of Formula (I), Formula (IA), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (IVA), Formula (IVB) or Formula (V) may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Dosage forms suitable for administration generally contain from about 1 mg to about 500 mg of active ingredient per unit. Appropriate coatings may be applied to increase palatability or delayed adsorption.
  • the present disclosure relates to a method of treatment of cancer, wherein the method includes the step of administration to a patient, in need of such treatment, a compound of Formula (I), Formula (IA), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (IVA), Formula (IVB) or Formula (V) as defined above, or a pharmaceutically acceptable salt, polymorph, solvate or stereoisomer thereof.
  • “Pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts, and base addition salts, of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. In particular, acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Exemplary acid addition salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulphamates, malonates, salicylates, propionates, methylene-bis-[beta]-hydroxynaphthoates, gentisates, isethionates, di-ptoluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, ptoluenesulphonates, cyclohexylsulphamates and quinateslaurylsul
  • references to the compounds of Formula (I), Formula (IA), Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula (IVA), Formula (IVB) or Formula (V) are meant to also include the pharmaceutically acceptable salts thereof.
  • “Therapeutically effective amount” or “effective amount” means the amount of the compound of formula (I) of the present invention or pharmaceutical composition containing a compound of formula (I) of the present invention that will elicit the biological or medical response of or desired therapeutic effect on a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compound as realized in accordance with the embodiments of the present disclosure, is any of:
  • the compound as realized in accordance with the embodiments of the present disclosure, is any of:
  • the compound as realized in accordance with the embodiments of the present disclosure, is any of:
  • the compound as realized in accordance with the embodiments of the present disclosure, is any of: N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3-(piperazin-1-yl)-1H-pyrrolo [2, 3- b] pyridin-4-amine.
  • the compounds of the present disclosure may be prepared by a number of processes as known to or appreciated by a person skilled in the pertinent art, and more specifically, as illustrated in the Examples section provided hereinbelow.
  • the symbols Ar 1 , R 1 , A, B, R 4 , P, Q, R, T, X, Y, Z, m and n when used in the Formula, are to be understood to represent those groups described above in relation to Formula (I) unless otherwise indicated.
  • Table 1 illustrates the compounds realized in accordance with embodiments of the present disclosure.
  • Step 2 Synthesis of 4-chloro-2-(4-fluorophenyl)-5-isopropylpyrimidine
  • Step 3 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-1H- pyrrolo [2,3-b] pyridin-4-amine
  • Step 5 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3- (piperazin-1-yl)-1H- pyrrolo[2,3- b]pyridin-4-amine
  • reaction mass was filtered to remove K 2 CO 3 and filtrate was concentrated on high vacuum pump and crude reaction mixture was purified by PREP-HPLC to give 0.050 g of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3-(piperazin-1-yl)-1 H- pyrrolo[2,3- b]pyridin-4-amine as pale yellow solid.
  • Compound was characterized by 1 H-NMR.
  • Step 6 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3- (piperazin-1-yl)-1H-pyrrolo [2, 3-b] pyridin-4-amine hydrochloride
  • Step 1 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3- (piperidin-1-yl)-1H-pyrrolo [2, 3-b] pyridin-4-amine
  • reaction mass was filtered to remove K 2 CO 3 and filtrate was concentrated on high vacuum pump and crude was purified by PREP-HPLC to give 0.018 g of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3-(piperidin-1-yl)-1H-pyrrolo [2, 3-b] pyridin-4-amine as white solid.
  • Step 2 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3- (4-methylpiperazin-1-yl)-1H-pyrrolo [2, 3-b] pyridin-4-amine hydrochloride
  • Step 1 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3- (piperidin-1-yl)-1H-pyrrolo [2, 3-b] pyridin-4-amine
  • Step 2 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3- (piperidin-1-yl)-1H-pyrrolo [2, 3-b] pyridin-4-amine hydrochloride
  • Step 1 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3- morpholino-1H-pyrrolo [2, 3-b] pyridin-4-amine
  • Step 2 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3- morpholino-1H-pyrrolo [2, 3-b] pyridin-4-amine hydrochloride
  • Step 1 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3- (1H-1, 2, 4-triazol-1-yl)-1H-pyrrolo [2, 3-b] pyridin-4-amine
  • Step 2 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3- (1H-1, 2, 4-triazol-1-yl)-1H-pyrrolo [2, 3-b] pyridin-4-amine hydrochloride
  • Example 7 and 8 Preparation of N-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-yl)-3-(2-methylpiperazin-1-yl)-1H-pyrrolo [2, 3-b] pyridin-4- amine hydrochloride (Compound No. 7) and N-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-yl)-3-(2-methylpiperazin-1-yl)-1H-pyrrolo [2, 3-b] pyridin-4- amine hydrochloride (Compound No.8)
  • Step 1 Synthesis of tert-butyl 4-(4-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-3-methylpiperazine-1- carboxylate
  • Step 2 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3- (2-methylpiperazin-1-yl)-1H-pyrrolo [2, 3-b] pyridin-4-amine hydrochloride
  • Step 3 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3- (2-methylpiperazin-1-yl)-1H-pyrrolo [2, 3-b] pyridin-4-amine hydrochloride
  • Step 1 Synthesis of (R)-tert-butyl 4-(4-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpiperazine-1- carboxylate: To solution of 3-bromo-N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine (0.100 g, 0.234 mmol, 1.0 eq) in 4 ml of DMF were added (R)-tert-butyl 2-methylpiperazine-1-carboxylate (0.234 g, 1.17 mmol, 5.0 eq) and K 2 CO 3 (0.162 g, 1.17 mmol, 5.0 eq ).
  • Step 2 Synthesis of (R)-N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)- 3-(3-methyl piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine hydrochloride: (R)-N-(2- (4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3-(3-methylpiperazin-1-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine (0.020 g, 0.036 mmol, 1.0 eq) was completely solubilized in ethanol (10 ml) and HCl in ethanol (5 ml of 1.23 M solution) was added to it.
  • Step 1 Synthesis of 4-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl) piperazin-2-one: To a solution of 3-bromo- N- (2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine (0.100 g, 0.235 mmol, 1.0 eq) in 4 ml of DMF, were added piperazin-2-one (0.117 g, 1.17 mmol, 5.0 eq) and K 2 CO 3 (0.064 g, 0.470 mmol, 2.0 eq ).
  • Step 2 Synthesis of 4-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl) piperazin-2-one formate: To a solution of 4- (4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl) piperazin-2-one (0.010 g, 0.022 mmol, 1.0 eq) in 10 ml of Methanol, was added 1 ml formic acid.
  • Example 11 Preparation of (S)-N-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-yl)-3-(3-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine hydrochloride (Compound No.11)
  • Step 1 Synthesis of (S)-tert-butyl 4-(4-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylpiperazine-1- carboxylate: To a solution of 3-bromo-N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine (0.100 g, 0.23 mmol, 1.0 eq) in 3 ml of DMF, were added (S)-tert-butyl 2-methylpiperazine-1-carboxylate (0.234 g, 1.17 mmol, 5.0 eq) and K 2 CO 3 (0.162 g, 1.17 mmol, 5.0 eq ).
  • Step 2 Synthesis of (S)-N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)- 3-(3-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine hydrochloride: To a solution of tert-butyl (S)-4-(4-((2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)-1H- pyrrolo[2,3-b]pyridin-3-yl)-2-methylpiperazine-1-carboxylate (0.067 g, 0.123 mmol, 1.0 eq.) in 2 ml of dioxane, was added 2 ml 4 M of dioxane in HCl.
  • Example 12 Preparation of 1-(4-((2-(4-fluorophenyl)-5- isopropylpyrimidin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-4- carboxamide formic acid (Compound No.12)
  • Step 1 Synthesis of 1-(4-((2-(4-fluorophenyl)-5-isopropylpyrimidin-4- yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-4-carboxamide: To a solution of 3- bromo- N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine (0.15 g, 0.35 mmol, 1.0 eq.) in 4 ml of DMF, was added piperidine-4-carboxamide (0.225 g, 1.76 mmol, 5.0 eq.) and K 2 CO 3 (0.243 g, 1.76 mmol, 5.0 eq.
  • Step 2 Synthesis of 1-(4-((2-(4-fluorophenyl)-5-isopropylpyrimidin-4- yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-4-carboxamide formic acid: To a solution of 1-(4-((2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)-1H-pyrrolo[2,3- b]pyridin-3-yl)piperidine-4-carboxamide (0.008 g, 0.123 mmol, 1.0 eq.) in 2 ml of methanol, was added 2 ml formic acid solution and reaction was stirred for 15 minutes and then solvent was evaporated and this procedure was repeated once.
  • Example 13 Preparation of 4-(4-((2-(4-fluorophenyl)-5- isopropylpyrimidin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-4-ol hydrochloride (Compound No.13)
  • Step 1 Synthesis of 4-(4-((2-(4-fluorophenyl)-5-isopropylpyrimidin-4- yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-4-ol: To a solution of N-(2-(4- fluorophenyl)-5-isopropylpyrimidin-4-yl)-1H-pyrrolo[2,3- b]pyridin-4-amine (0.1 g, 0.28 mmol, 1.0 eq.) in 120 ml of ethanol, was added piperidin-4-one (0.38 g, 2.88 mmol, 10.0 eq.) and powdered KOH (0.32 g, 5.7 mmol, 20.0 eq.).
  • Step 2 Synthesis of 4-(4-((2-(4-fluorophenyl)-5-isopropylpyrimidin-4- yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-4-ol hydrochloride: To a solution of 1-(4-((2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridin-3- yl)piperidine-4-carboxamide (0.011 g, 0.024 mmol, 1.0 eq.) in 2 ml of dioxane, was added 2 ml dioxane HCl solution and reaction was stirred for 15 minutes and then solvent was evaporated and this procedure was repeated twice.
  • Step 1 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3- (3-methylmorpholino)-1H-pyrrolo [2, 3-b] pyridin-4-amine: To a solution of 3-bromo- N- (2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-1 H-pyrrolo[2,3- b]pyridin-4-amine (0.100 g, 0.234 mmol, 1.0 eq) in 3 ml of DMF, were added 3-methylmorpholine (0.118 g, 1.17 mmol, 5.0 eq) and K 2 CO 3 (0.097 g, 0.702mmol, 3.0 eq ).
  • reaction mass was heated at 100 °C for 1 hour under microwave. After completion of reaction (LCMS monitoring), reaction mass was filtered to remove K 2 CO 3 and filtrate was concentrated on high vacuum pump and crude reaction mixture was purified by PREP-HPLC to give 0.015 g of N-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-yl)-3-(3-methylmorpholino)-1H-pyrrolo [2, 3-b] pyridin-4-amine as pale yellow solid.
  • Step 2 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3- (3-methylmorpholino)-1H-pyrrolo [2, 3-b] pyridin-4-amine hydrochloride: To the clear solution of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-3-(3-methylmorpholino)-1H- pyrrolo [2, 3-b] pyridin-4-amine (0.015 g, 0.033 mmol, 1.0 eq.) in 5 ml of ethanol was added 5 ml of 1.23 M solution of HCl in ethanol.
  • Example 15 Preparation of 3-(4-aminopiperidin-1-yl)-N-(2-(4- fluorophenyl)-5-isopropylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 1 Synthesis of tert-butyl 1-(4-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-4-yl carbamate: To a solution of 3-bromo- N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-1 H- pyrrolo[2,3- b]pyridin-4-amine (0.100 g, 0.234 mmol, 1.0 eq) in 3 ml of DMF, were added tert-butyl piperidin-4-ylcarbamate (0.234 g, 1.17 mmol, 5.0 eq) and K 2 CO 3 (0.064 g, 0.468 mmol, 3.0 eq ).
  • reaction mass was heated at 100 °C for 1 hour under microwave. After completion of reaction (LCMS monitoring), reaction mass was filtered to remove K 2 CO 3 and filtrate was concentrated on high vacuum pump and crude reaction mixture was purified by PREP-HPLC to give 0.019 g of tert-butyl 1-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-4-ylcarbamate as white solid.
  • 1 H NMR 400 MHz, DMSO-d 6 ): ⁇ 11.38 (br. s., 1H), 9.89 (br.
  • Step 2 Synthesis of 3-(4-aminopiperidin-1-yl)-N-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine hydrochloride: To the clear solution of tert-butyl 1-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-ylamino)-1H- pyrrolo[2,3-b]pyridin-3-yl)piperidin-4-ylcarbamate (0.010 g, 0.018 mmol, 1.0 eq.) in 5 ml of ethanol was added 5 ml of 1.23 M solution of HCl in ethanol.
  • Example 16 Preparation of 2-(4-((2-(4-fluorophenyl)-5- isopropylpyrimidin-4-yl) amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethyl-2- oxoacetamide (Compound No.16)
  • Step-1 Synthesis of methyl 2-(4-((2-(4-fluorophenyl)-5- isopropylpyrimidin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetate: To the solution of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4- amine (0.6 g, 1.72 mmol, 1.0 eq.) in CH 2 Cl 2 (100 ml) cooled at 0 °C were added aluminum trichloride (1.14 g, 8.6 mmol, 5.0 eq.) and methyl 2-chloro-2-oxoacetate (3.11 g, 28.6 mmol, 16.6 eq.
  • Step-2 Synthesis of 2-(4-((2-(4-fluorophenyl)-5-isopropylpyrimidin-4- yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetamide hydrochloride: To the solution of methyl 2-(4-((2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)-1H-pyrrolo[2,3- b]pyridin-3-yl)-2-oxoacetate (0.08 g, 0.18 mmol, 1.0 eq.) in methanol (0.2 ml) was added ammonia in methanol (6 M, 2 ml) and reaction was heated in microwave at 100 °C for 50 min, keeping cooling temperature 40 °C.
  • Example 18 Preparation of Synthesis of 2-(4-((2-(5-chloro-2- fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N- methyl-2-oxoacetamide hydrochloride (Compound No.18)
  • Step-1 and Step-2 Synthesis of 2-(5-chloro-2-fluorophenyl)-5- isopropylpyrimidin-4-ol: To the solution of 5-chloro-2-fluorobenzonitrile (5.0 g, 32.0 mmol, 1.0 eq.) in CH 2 Cl 2 (500 ml) at 0 °C NaHDMS (17.68 g, 96.0 mmol, 3eq.) was added drop wise. The reaction was stirred at 0 °C for 30 min and then it was warmed to room temperature and then stirring was continued for 2 h. Solvent was evaporated and residue was washed with water and then extracted with ethyl acetate thrice.
  • Step-3 Synthesis of 4-chloro-2-(5-chloro-2-fluorophenyl)-5- isopropylpyrimidine: To the suspension of 2-(5-chloro-2-fluorophenyl)-5- isopropylpyrimidin-4-ol (3.0 g, 11.2 mmol, 1 eq.) in 15 ml thionyl chloride taken in 50 ml sealed tube was added 2-3 drops of DMF. Reaction mass was heated at 85 °C for 1.5 h. Progress of reaction was monitored by TLC. Upon completion of reaction thionyl chloride was removed under reduced pressure.
  • Residue was dissolved in ethyl acetate 150 ml, and then organic layer was washed with 10% NaHCO 3 twice to remove remaining thionyl chloride followed by water and brine solution. Dried over anhydrous Na 2 SO 4 , and solvent was evaporated under reduced pressure at low temperature to obtain 3 g of 4-chloro-2-(5- chloro-2-fluorophenyl)-5-isopropylpyrimidine as white solid. Product was confirmed by 1H- NMR.
  • Step-4 Synthesis of N-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin- 4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine: To the solution of compound 4-amino 7-azaindole (0.5 g, 3.75 mmol, 1.0 eq.) in 5 ml DMF cooled at -0 °C were added 4-chloro-2-(5-chloro-2- fluorophenyl)-5-isopropylpyrimidine (1.07 g, 3.75 mmol, 1.0 eq.) followed by drop wise addition of NaHMDS solution (4.13 g (13.05 ml), 22.5mmol, 35% in THF, 6 eq.) in two lots, under N 2 atm.
  • reaction mass was continued at same temperature for 5h. After completion of reaction (TLC monitoring), reaction mass was poured in 250 g of ice cooled water. Resulting solid was filtered out to get 1.4 g of crude product. Crude material was purified by silica gel column chromatography (100-200) mesh silica with 0-3% MeOH: DCM to obtain 1.2 g of N- (2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine, product was characterized by 1 H-NMR and LCMS.
  • Step-5 Synthesis of 2-(4-((2-(5-chloro-2-fluorophenyl)-5- isopropylpyrimidin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-2- oxoacetamide hydrochloride: To the solution of N-(2-(5-chloro-2-fluorophenyl)-5- isopropylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (0.7 g, 1.8 mmol, 1.0 eq.) in CH 2 Cl 2 (50 ml) cooled at 0 °C were added aluminum trichloride (1.22 g, 9.1 mmol, 5.0 eq.) and methyl 2-chloro-2-oxoacetate (3.3 g, 30.0 mmol, 16.6 eq.
  • reaction mass was allowed to warm at room temperature and then stirred for 48 h. After completion reaction (LCMS monitoring) methanol (30 ml) was added to reaction mass and again it was stirred at overnight. Then methanol was removed and reaction mixture was stirred in THF (50 ml) and 2 M NaOH solution for 12 h, then solvent was evaporated and residue was acidified using 2 M HCl again extracted with ethyl acetate thrice.
  • Step-1 Synthesis of 2-(4,6-dichloropyridin-3-yl)propan-2-ol: To solution of methyl 4,6-dichloronicotinate (4.5 g, 22 mmol, 1.0 eq) in 40 ml of THF cooled at 0 °C was added solution of MeMgBr (25.4 ml, 76 mmol, 3.5 eq, 3 M in ether) under nitrogen atmosphere. Reaction mass was stirred at same temperature for 4h. After completion of reaction (TLC monitoring) excess MeMgBr was quenched by saturated NH 4 Cl solution. Desired product was extracted from aq.
  • Step-2 Synthesis of 2,4-dichloro-5-(prop-1-en-2-yl)pyridine: To solution of 2-(4,6-dichloropyridin-3-yl)propan-2-ol (4.5 g, 21 mmol, 1.0 eq) in 100 ml of Toluene was added pTSA (4.1 g, 24 mmol, 1.1 eq) under nitrogen atmosphere. Reaction mass was heated to reflux under dean stark condition to remove water. After completion of reaction toluene was removed by distillation and then crude product was dissolved in ethyl acetate 250 ml. Organic layer was washed with brine (2 ⁇ 50 ml) and water (2 ⁇ 50 ml).
  • Step-3 Synthesis of 4-chloro-2-(4-fluorophenyl)-5-(prop-1-en-2- yl)pyridine: Solution of (4-fluorophenyl)boronic acid (1.1 g, 8.01 mmol, 1.0 eq), 2,6- dichloro-3-(prop-1-en-2-yl) pyridine (1.5 g, 8.01 mmol, 1.0 eq) and NaHCO 3 (2.0 g, 24.03 mmol, 3.0 eq) in 60 ml of DMF and 15 ml of water was purged with N 2 gas for 15 min.
  • (4-fluorophenyl)boronic acid 1.1 g, 8.01 mmol, 1.0 eq
  • 2,6- dichloro-3-(prop-1-en-2-yl) pyridine 1.5 g, 8.01 mmol, 1.0 eq
  • NaHCO 3 2.0 g, 24.03 mmol, 3.0 eq
  • Step-4 Synthesis of N-(2-(4-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4- yl)-1H-pyrrolo[2,3-b]pyridin-4-amine: Solution of 4-chloro-2-(4-fluorophenyl)-5-(prop-1- en-2-yl)pyridine (1.2 gm, 4.84 mmol, 1.0 eq), 1H-pyrrolo[2,3- b]pyridin-4-amine (0.646 g, 4.84 mmol, 1.0 eq) and K 3 PO 4 (2.0 g, 9.46 mmol, 2.0 eq) in 20 ml of dioxane was purged with N 2 gas for 15 min.
  • Step-5 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyridin-4-yl)-1H- pyrrolo[2,3-b]pyridin-4-amine: To solution of crude N-(2-(4-fluorophenyl)-5-(prop-1-en-2- yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.0 g, 2.90 mmol, 1.0 eq) in 100 ml of THF was added Pd/C (300 Mg, 10% ). Reaction mass was stirred at rt under H 2 atmosphere for 16 h.
  • Step-6 Synthesis of 2-(4-((2-(4-fluorophenyl)-5-isopropylpyridin-4-yl) amino)-1H-pyrrolo [2,3-b]pyridin-3-yl)-2-oxoacetamide: To the solution of N-(2-(4- fluorophenyl)-5-isopropylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (0.7 g, 1.8 mmol, 1.0 eq.) in 300 ml CH 2 Cl 2 cooled at 0 °C was added aluminum trichloride (1.21 g, 9.1 mmol, 5.0 eq.) and methyl 2-chloro-2-oxoacetate (1.98 g, 18.0 mmol, 10 eq.) under N 2 atmosphere.
  • reaction mass was allowed to warm at room temperature and then stirred for 48 h. After completion reaction (LCMS monitoring) methanol (50 ml) was added to reaction mass and again it was stirred for overnight. Then methanol was removed by distillation and crude was taken in 250 ml of ethyl acetate. Organic layer was washed by water twice (2 ⁇ 100 ml) and brine solution twice (2 ⁇ 100 ml). Dried over anhydrous Na 2 SO 4 , and solvent was evaporated under reduced pressure.
  • LCMS monitoring methanol (50 ml) was added to reaction mass and again it was stirred for overnight. Then methanol was removed by distillation and crude was taken in 250 ml of ethyl acetate. Organic layer was washed by water twice (2 ⁇ 100 ml) and brine solution twice (2 ⁇ 100 ml). Dried over anhydrous Na 2 SO 4 , and solvent was evaporated under reduced pressure.
  • Step-7 Synthesis of 2-(4-((2-(4-fluorophenyl)-5-isopropylpyridin-4- yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetamide hydrochloride: To the clear solution of 2-(4-((2-(4-fluorophenyl)-5-isopropylpyridin-4-yl)amino)-1H-pyrrolo[2,3- b]pyridin-3-yl)-2-oxoacetamide (0.024 g, 0.057 mmol, 1.0 eq) in 8 ml of methanol was added 5 ml of solution of HCl in methanol.
  • Example 20 Preparation of N-butyl-2-(4-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-oxoacetamide hydrochloride (Compound No.20)
  • Step-1 Synthesis of N-butyl-2-(4-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-oxoacetamide: To solution of methyl 2-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-oxoacetate (0.150 g, 0.346 mmol, 1.0 eq) in 15 ml of DMF was added n- BuNH 2 (0.45 ml, 4.20 mmol, 5.0 eq).
  • Reaction mass was heated at 100 °C for 1h under microwave. After completion of reaction (LCMS monitoring), DMF was removed by distillation using high vacuum pump and crude was purified by PREP-HPLC to give 0.025 g of N-butyl-2-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-oxoacetamide as white solid.
  • Step-2 Synthesis of N-butyl-2-(4-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-oxoacetamide hydrochloride: To the clear solution of N-butyl-2-(4-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-oxoacetamide (0.022 g, 0.043 mmol, 1.0 eq) in 10 ml of ethanol was added 5 ml of 1.23 M solution of HCl in ethanol.
  • Step-1 Synthesis of 2-(4-((2-(4-fluorophenyl)-5-isopropylpyridin-4- yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-2-oxoacetamide: Crude compound methyl 2-(4-((2-(4-fluorophenyl)-5-isopropylpyridin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridin- 3-yl)-2-oxoacetate (0.1 g, 0.231 mmol, 1.0 eq) was taken in 1 ml of methanol and then 5 ml of 2 M methyl amine in THF was added to it.
  • reaction mixture was heated at 100 °C for 1h in microwave. After completion of reaction solvent was removed by distillation and crude was purified by PREP-HPLC to give 24 mg of 2-(4-((2-(4-fluorophenyl)-5-isopropylpyridin- 4-yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-2-oxoacetamide.
  • Step-2 Synthesis of 2-(4-((2-(4-fluorophenyl)-5-isopropylpyridin-4- yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-2-oxoacetamide hydrochloride: To the clear solution of 2-(4-((2-(4-fluorophenyl)-5-isopropylpyridin-4-yl)amino)-1H- pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-2-oxoacetamide (0.024 g, 0.057 mmol, 1.0 eq) in 8 ml of methanol was added 5 ml of solution of HCl in methanol.
  • Example 22 Preparation of 1-(4-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-morpholinoethane-1, 2-dione hydrochloride (Compound No.22)
  • Step-1 Synthesis of 2-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-oxoacetic acid: To a solution of methyl 2-(4- (2-(4-fluorophenyl)-5-isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2- oxoacetate (1.5 g, 3.46 mmol, 1.0 eq) in 100 ml system of THF: MeOH: H2O (3:1:1) was slowly added 15 ml of 2 M aq.NaOH solution at 0 °C.
  • Step-2 Synthesis of 1-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-morpholinoethane-1, 2-dione: To solution of 2-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3- yl)-2-oxoacetic (0.100 g, 0.238 mmol, 1.0 eq) in 15 ml of DMF were added NEt 3 (0.1 ml, 0.715 mmol, 3.0 eq) and PyBOP (0.160 g, 0.309 mmol, 1.3 eq) at rt.
  • reaction mass was allowed to stirred at rt for 15 min and then morpholine (0.04 ml, 0.476 mmol, 2.0 eq) was added slowly drop wise. Reaction was stirred for 6 h under N 2 atm. After completion of reaction DMF was removed by high vacuum distillation and product was purified by PREP- HPLC to get 0.019 g of 1-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-ylamino)-1H- pyrrolo [2, 3-b] pyridin-3-yl)-2-morpholinoethane-1, 2-dione as white solid.
  • Step-3 Synthesis of 1-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-morpholinoethane-1, 2-dione hydrochloride : To the clear solution of 1-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-morpholinoethane-1, 2-dione (0.019 g, 0.038 mmol, 1.0 eq) in 10 ml of ethanol was added 5 ml of 1.23 M solution of HCl in ethanol.
  • Example 23 Preparation of 1-(4-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-(piperazin-1-yl) ethane-1, 2-dione hydrochloride (Compound No.23)
  • Step-1 Synthesis of 1-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-(piperazin-1-yl) ethane-1, 2-dione: To solution of 2-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-oxoacetic (0.100 g, 0.238 mmol, 1.0 eq) in 15 ml of DMF were added NEt 3 (0.1 ml, 0.714 mmol, 3.0 eq) and PyBOP (0.161 g, 0.309 mmol, 1.3 eq) at rt.
  • reaction mass was allowed to stirred at rt for 15 min and then piperazine (0.040 g, 0.476 mmol, 2.0 eq) was added slowly drop wise. Reaction was stirred for 6h under N 2 atm. After completion of reaction DMF was removed by high vacuum distillation and product was purified by PREP- HPLC to get 0.030 g of 1-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-ylamino)-1H- pyrrolo [2, 3-b] pyridin-3-yl)-2-(piperazin-1-yl) ethane-1, 2-dione as white solid.
  • Step-2 Synthesis of 1-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-(piperazin-1-yl) ethane-1, 2-dione hydrochloride: To the clear solution of 1-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-(piperazin-1-yl) ethane-1, 2-dione (0.030 g, 0.061 mmol, 1.0 eq) in 10 ml of ethanol was added 5 ml of 1.23 M solution of HCl in ethanol.
  • Example 24 Preparation of 1-(4-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-(4-methylpiperazin- 1-yl) ethane-1, 2-dione hydrochloride (Compound No.24)
  • Step-1 Synthesis of 1-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-(4-methylpiperazin-1-yl) ethane-1, 2-dione: To solution of 2-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-oxoacetic (0.150 g, 0.357 mmol, 1.0 eq) in 15 ml of DMF were added NEt 3 (0.15 ml, 1.07 mmol, 3.0 eq) and PyBOP (0.240 g, 0.464 mmol, 1.3 eq) at rt.
  • Step-2 Synthesis of 1-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-(4-methylpiperazin-1-yl) ethane-1, 2-dione hydrochloride: To the clear solution of 1-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-(4-methylpiperazin-1-yl) ethane-1, 2-dione (0.035 g, 0.0698 mmol, 1.0 eq) in 10 ml of ethanol was added 5 ml of 1.23 M solution of HCl in ethanol.
  • Example 25 Preparation of 2-(4-((5-isopropyl-2-(4-methoxyphenyl) pyrimidin-4-yl) amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetamide hydrochloride (Compound No.25)
  • Step-1 Synthesis of 4-chloro-5-isopropyl-2-(4-methoxyphenyl) pyrimidine: To the solution of 4-methoxybenzimidamide hydrochloride (2.0 g, 10.70 mmol, 1.0 eq.) in ethanol (50 ml), ethyl 2-formyl-3-methylbutanoate (2.2 g, 13.91 mmol, 1.3 eq.) was added followed by NaHCO3 (2.6 g, 32.13 mmol, 3.0 eq). Reaction mixture was refluxed at 85 °C for 16 h. The progress of reaction was monitored by TLC and LCMS. Upon completion of reaction ethanol was removed under reduced pressure to get crude product.
  • Step-2 Synthesis of N-(5-isopropyl-2-(4-methoxyphenyl) pyrimidin-4-yl)- 1 H-pyrrolo[2,3- b]pyridin-4-amine: To the solution of compound 4-amino 7-azaindole (0.608 g, 4.56 mmol,1.0 eq) in 5 ml DMF cooled at -5° were added 4-chloro-5-isopropyl-2- (4-methoxyphenyl)pyrimidine (1.2 g ,4.56 mmol, 1.0 eq) followed by slow drop wise addition of solution of NaHMDS (14 ml,27.39 mmol,35% in THF) in two lots, under N2 atm.
  • 4-amino 7-azaindole 0.608 g, 4.56 mmol,1.0 eq
  • 4-chloro-5-isopropyl-2- (4-methoxyphenyl)pyrimidine 1.2 g ,4.56
  • reaction mass was allowed to warm at room temperature and then stirred for 48 h. After completion reaction (LCMS monitoring) methanol (50 ml) was added to reaction mass and again it was stirred at overnight. Then methanol was removed by distillation and crude was taken in 250 ml of ethyl acetate. Organic layer was washed by water twice (2 ⁇ 100 ml) and brine solution twice (2 ⁇ 100 ml).
  • Step-4 Synthesis of 2-(4-((5-isopropyl-2-(4-methoxyphenyl) pyrimidin-4- yl) amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetamide hydrochloride: To the clear solution of 2-(4-((5-isopropyl-2-(4-methoxyphenyl) pyrimidin-4-yl) amino)-1 H-pyrrolo[2,3- b]pyridin-3-yl)-2-oxoacetamide (0.035 g, 0.081 mmol, 1.0 eq) in 10 ml of ethanol was added 5 ml of 1.23 M solution of HCl in ethanol.
  • Example 26 Preparation of 2-(4-((5-isopropyl-2-phenylpyrimidin-4- yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetamide hydrochloride (Compound No.26)
  • Step-1 Synthesis of 5-isopropyl-2-(4-methoxyphenyl) pyrimidin-4-ol: To the solution of benzimidamide hydrochloride (2.0 g, 12.8 mmol, 1.0 eq.) and ethyl 2-formyl- 3-methylbutanoate (2.02 g, 12.8 mmol, 1 eq.) in ethanol (40 ml) was added NaHCO 3 (3.23 g, 38.4 mmol, 3.0 eq.). Reaction mixture was refluxed at 85 °C for 16 h. The progress of reaction was monitored by TLC and LCMS. Upon completion the ethanol was removed under reduced pressure to get crude product. Crude material was triturated with n-pentane to give 2.5 g of 5-isopropyl-2-phenylpyrimidin-4-ol. LCMS (M+1): 215.11
  • Step-2 Synthesis of 4-chloro-5-isopropyl-2-phenylpyrimidine: To the suspension of 5-isopropyl-2-(4-methoxyphenyl) pyrimidin-4-ol (1.2 g, 5.6 mmol) in 12 ml thionyl chloride taken in 100 ml sealed tube was added 2-3 drops of DMF. Reaction mmixture was heated at 90 °C for 2h. Progress of reaction was monitored by TLC. Upon completion of reaction thionyl chloride was removed under reduced pressure.
  • Step-3 Synthesis of N-(5-isopropyl-2-phenylpyrimidin-4-yl)-1H-pyrrolo
  • [2,3-b]pyridin-4-amine To the solution of compound 4-amino 7-azaindole (0.550 g, 4.1 mmol, 1.0 eq.) in 2 ml DMF cooled at -5 °C and then 4-chloro-5-isopropyl-2- phenylpyrimidine (0.959 g, 4.1 mmol, 1.0 eq.) was added followed by drop wise addition of solution of NaHMDS (14 ml, 27.39 mmol, 35 % in THF) in two lots, under N 2 atm. Reaction mixture was continued at same temperature for 5 h. After completion of reaction (TLC monitoring), reaction mass was poured in 1 lit of ice cooled water.
  • Step-4 Synthesis of methyl 2-(4-((5-isopropyl-2-phenylpyrimidin-4- yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetate: To the solution of N-(5-isopropyl- 2-phenylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (0.43 g, 1.3 mmol, 1.0 eq.) in 25 ml CH 2 Cl 2 cooled at 0 °C was added aluminum trichloride (0.87 g, 6.5 mmol, 5.0 eq.) and methyl 2-chloro-2-oxoacetate (2.35 g, 21.6 mmol, 16.6 eq.) under N 2 atmosphere.
  • Reaction mixture was allowed to warm at room temperature and then stirred for 48 h. After completion reaction (LCMS monitoring) methanol (50 ml) was added to reaction mixture at 0 °C and again it was stirred at room temperature for 18 h. Organic solvent was removed by distillation and crude was taken in 250 ml of ethyl acetate. Organic layer was washed by water twice (2 ⁇ 100 ml) and brine solution twice (2 ⁇ 100 ml).
  • Step-5 Synthesis of 2-(4-((5-isopropyl-2-phenylpyrimidin-4-yl)amino)- 1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetamide: Solution of crude methyl 2-(4-((5- isopropyl-2-(4-methoxyphenyl) pyrimidin-4-yl) amino)-1 H-pyrrolo [2, 3- b] pyridin-3-yl)-2- oxoacetate (0.2 g, 0.4 mmol, 1.0 eq.) in 3 ml of methanolic ammonia was heated at 100 °C for 1h in microwave.
  • Step-6 Synthesis of 2-(4-((5-isopropyl-2-phenylpyrimidin-4-yl)amino)- 1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetamide hydrochloride: To the clear solution of 2- (4-((5-isopropyl-2-phenylpyrimidin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- oxoacetamide (9 mg, 0.025 mmol, 1.0 eq.) in 2 ml of ethanol was added 2 ml of 1.23 M solution of HCl in ethanol.
  • Example 27 Preparation of 2-(4-(6-(4-fluorophenyl)-3-isopropylpyridin- 2-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-oxoacetamide hydrochloride (Compound No.27)
  • Step-1 Synthesis of 2-(2, 6-dichloropyridin-3-yl) propan-2-ol: To solution of methyl 2, 6-dichloronicotinate (4.5 g, 22 mmol, 1.0 eq) in 40 ml of THF cooled at 0 °C was added solution of MeMgBr (25.4 ml, 76 mmol, 3.5 eq, 3 M in ether) under nitrogen atmosphere. Reaction mass was stirred at same temperature for 4 h. After completion of reaction (TLC monitoring) excess MeMgBr was quenched by saturated NH 4 Cl solution. Desired product was extracted from aq.
  • Step-2 Synthesis of 2, 6-dichloro-3-(prop-1-en-2-yl) pyridine: To solution of methyl 2-(2, 6-dichloropyridin-3-yl) propan-2-ol (4.5 g, 21 mmol, 1.0 eq) in 100 ml of Toluene was added pTSA (4.1 g, 24 mmol, 1.1 eq) under nitrogen atmosphere. Reaction mass was heated to reflux under dean stark condition to remove water. After completion of reaction toluene was removed by distillation and then crude product was dissolved in ethyl acetate 250 ml. Organic layer was washed with brine (2 ⁇ 50 ml) and water (2 ⁇ 50 ml) .
  • pTSA 4.1 g, 24 mmol, 1.1 eq
  • Step-3 Synthesis of 2-chloro-6-(4-fluorophenyl)-3-(prop-1-en-2-yl) pyridine: Solution of (4-fluorophenyl)boronic acid (1.1 g, 8.01 mmol, 1.0 eq), 2,6-dichloro- 3-(prop-1-en-2-yl) pyridine (1.5 g, 8.01 mmol, 1.0 eq) and NaHCO 3 (2.0 g, 24.03 mmol, 3.0 eq) in 60 ml of DMF and 15 ml of water was purged with N 2 gas for 15 min.
  • (4-fluorophenyl)boronic acid 1.1 g, 8.01 mmol, 1.0 eq
  • 2,6-dichloro- 3-(prop-1-en-2-yl) pyridine 1.5 g, 8.01 mmol, 1.0 eq
  • NaHCO 3 2.0 g, 24.03 mmol, 3.0 eq
  • reaction mass was poured in 600 ml of ice water and product was extracted in ethyl acetate.
  • Step-4 Synthesis of N-(6-(4-fluorophenyl)-3-(prop-1-en-2-yl) pyridin-2- yl)-1 H-pyrrolo[2,3- b]pyridin-4- Amine: Solution of 2-chloro-6-(4-fluorophenyl)-3-(prop- 1-en-2-yl) pyridine (1.2 g, 4.84 mmol, 1.0 eq), 1H-pyrrolo[2,3- b]pyridin-4-amine (0.646 g, 4.84 mmol, 1.0 eq) and K3PO4 (2.0 g, 9.46 mmol, 2.0 eq) in 20 ml of dioxane was purged with N2 gas for 15 min.
  • reaction mass was again purged with N2 gas for 15 min. Then reaction mass was heated at 110 °C for 48 h. After completion of reaction, reaction mass was poured in 200 ml of ice water and product was extracted in ethyl acetate.
  • Step-5 Synthesis of N-(6-(4-fluorophenyl)-3-isopropylpyridin-2- yl)-1 H- pyrrolo[2,3- b]pyridin-4-amine: To solution of N-(6-(4-fluorophenyl)-3-isopropylpyridin-2- yl)-1 H-pyrrolo[2,3- b]pyridin-4-amine (1.0 g, 2.90 mmol, 1.0 eq) in 100 ml of THF was added Pd/C (300 Mg, 10% ). Reaction mass was stirred at rt under H 2 atmosphere for 16 h.
  • reaction mass was filtered through celite bed and filtrate was concentrated to get 0.9 g of N-(6-(4-fluorophenyl)-3-isopropylpyridin-2- yl)-1 H-pyrrolo[2,3- b]pyridin-4-amine as dark solid.
  • reaction mass was allowed to warm at room temperature and then stirred for 48h. After completion reaction (LCMS monitoring) methanol (50 ml) was added to reaction mass and again it was stirred for overnight. Then methanol was removed by distillation and crude was taken in 250 ml of ethyl acetate. Organic layer was washed by water twice (2 ⁇ 100 ml) and brine solution twice (2 ⁇ 100 ml). Dried over anhydrous Na 2 SO 4 , and solvent was evaporated under reduced pressure.
  • LCMS monitoring methanol (50 ml) was added to reaction mass and again it was stirred for overnight. Then methanol was removed by distillation and crude was taken in 250 ml of ethyl acetate. Organic layer was washed by water twice (2 ⁇ 100 ml) and brine solution twice (2 ⁇ 100 ml). Dried over anhydrous Na 2 SO 4 , and solvent was evaporated under reduced pressure.
  • Step-7 Synthesis of 2-(4-(6-(4-fluorophenyl)-3-isopropylpyridin-2- ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-oxoacetamide: Solution of methyl 2-(4-(6-(4- fluorophenyl)-3-isopropylpyridin-2-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-oxoacetate (0.100 g, 0.231 mmol, 1.0 eq) in 15 ml of methanolic ammonia was heated at 100 °C for 1 h in microwave.
  • Step-8 Synthesis of 2-(4-(6-(4-fluorophenyl)-3-isopropylpyridin-2- ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-oxoacetamide hydrochloride: To the clear solution of 2-(4-(6-(4-fluorophenyl)-3-isopropylpyridin-2-ylamino)-1H-pyrrolo [2, 3-b] pyridin-3-yl)-2-oxoacetamide (0.025 g, 0.059 mmol, 1.0 eq) in 10 ml of ethanol was added 5 ml of 1.23M solution of HCl in ethanol.
  • Step-1 Synthesis of N-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4-yl)-1H- indol-4-amine: To the solution of compound 1H-indol-4-amine (1.04 g, 7.91 mmol, 1.1 eq) in 5 ml DMF cooled at -5 °C were added 4-chloro-2-(4-fluorophenyl)-5-isopropylpyrimidine (1.8 g, 7.19 mmol) followed by slow drop wise addition of NaHMDS solution (22.7 ml, 43.14 mmol, 35 % in THF) in two lots, under N 2 atmosphere. Reaction mass was continued at same temperature for 5 h.
  • reaction mass was poured in 500 ml of ice cooled water. Resulting solid product was filtered out, which was further purified by flash column chromatography to give 0.6 g of N-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-yl)-1H-indol-4-amine as pale pink solid.
  • reaction mass was allowed to warm at room temperature and then stirred for 48 h. After completion reaction (LCMS monitoring) methanol (20 ml) was added to reaction mass and again it was stirred for overnight. Then methanol was removed by distillation and crude material was taken in 100 ml of ethyl acetate. Organic layer were washed by water twice (2 ⁇ 100 ml) and brine solution twice (2 ⁇ 100 ml).
  • Step-3 Synthesis of 2-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-indol-3-yl)-2-oxoacetamide: Solution of methyl 2-(4-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-ylamino)-1H-indol-3-yl)-2-oxoacetate (0.6 g, 1.38 mmol, 1.0 eq) in 10 ml of methanolic ammonia was heated at 100 °C for 1 h in microwave.
  • Step-4 Synthesis of 2-(4-(2-(4-fluorophenyl)-5-isopropylpyrimidin-4- ylamino)-1H-indol-3-yl)-2-oxoacetamide hydrochloride: 2-(4-(2-(4-fluorophenyl)-5- isopropylpyrimidin-4-ylamino)-1H-indol-3-yl)-2-oxoacetamide (0.035 g, 0.083 mmol, 1.0 eq) was completely solubilized in 15 ml of ethanol and and HCl in ethanol (5 ml of 1.23 M solution) was added to it.
  • Example 29 Preparation of 2-(4-((2-(4-fluorophenyl)-5- isopropylpyrimidin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-2- oxoacetamide hydrochloride (Compound No.29):
  • ALK5 Kinase assay for IC 50 determination [000190] ALK5 Kinase assay for IC 50 determination:
  • IC 50 values of compounds against TGFß kinase was determined by LanthaScreenTM Terbium Labeled TR-FRET assay. Kinase assays were performed in 1X kinase buffer (#PV6135, Invitrogen, Life Technologies Grand Island, NY) where total reaction volume was 10 ⁇ L in low-volume 384-well plates (#4511,Corning).
  • % activity of test samples was calculated as (Sample–Min) x100 / (Max– Min). [Max: DMSO control, complete reaction with enzyme with DMSO and Min: No enzyme with DMSO]. Percent inhibition (100–% activity) was fitted to the“four-parameter logistic model” in XLfit for determination of IC 50 values.
  • IC 50 values of compounds against MAPK14/P38a kinase were determined by Lanthascreen based TR-FRET assay. Kinase reactions were performed in a 10 ⁇ L volume in low-volume 384-well plates. The concentration of substrate was maintained at 400 nM in the assay, and the kinase reaction buffer (1X; Cat # PV3189, ThermoFisher) consisted of 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, and 1 mM EGTA.
  • Table 2 illustrates percentage Inhibition of enzyme activity (ALK-5 and P38 Alpha MAP kinase) at 100nM concentration of compounds:
  • Table 3 illustrates IC 50 value of dual ALK-5 and P38 Alpha MAP kinase inhibitor compounds
  • Table 4 illustrates percentage Inhibition of enzyme activity (P38 Alpha MAP kinase) at 100nM concentration of compounds as well as IC 50 value towards ALK-5 inhibition.
  • Table 5 illustrates compounds exhibiting dual inhibitory activity with their IC 50 value towards ALK-5 inhibition.
  • MIA PaCa-2 ATCC®CRL-1420TM
  • Panc-1 CL-1469TM
  • DMEM Dulbec-1
  • FBS FBS
  • Cat # 16000044 Gibco for Panc-1
  • Horse Serum Cat # 16050122
  • Table 5 illustrates compounds exhibiting inhibitory activity with their IC 50 value towards MIA PaCa-2 and Panc-1 cell lines inhibition.
  • compositions of the present invention are bases and salts of such compounds may be formed with acids, for example, a salt with inorganic acid such as hydrochloric acid or a salt with organic acid such as trifluoroacetic acid.
  • the compounds of this invention may be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature or exemplified in the experimental procedures. These schemes, therefore, are not limited by the compounds listed nor by any particular substituents employed for illustrative purposes and in no way limit the scope of the invention.
  • the present disclosure provides dual ALK5/P38 ⁇ kinase inhibitor compounds.
  • the present disclosure provides a method of synthesis of compounds that possess dual ALK5/P38 ⁇ kinase inhibitory activity.
  • the present disclosure provides method of treatment of conditions associated with excessive activity of any or a combination of ALK5 and P38 ⁇ kinase.
  • the present disclosure provides method of treatment of cancer by administering at least one agent that inhibit any or a combination of ALK5 and P38 ⁇ MAP kinase.
  • the present disclosure provides method of treatment of inflammatory disease/ailment by administering at least one agent that inhibit any or a combination of ALK5 and P38 ⁇ MAP kinase.
  • the present disclosure provides method of treatment of cancer by administering at least one agent that inhibit any or a combination of ALK5 and P38 ⁇ MAP kinase in combination with at least one immunotherapeutic agent.
  • the present disclosure provides method of treatment of inflammatory disease by administering at least one agent that inhibit any or a combination of ALK5 and P38 ⁇ MAP kinase in combination with at least one anti-inflammatory agent.
  • compositions containing at least one compound that inhibit ALK5 and P38 ⁇ MAP kinase are provided.
  • compositions containing at least one compound possessing dual inhibitory activity against ALK5 and P38 ⁇ MAP kinase that find utility in treatment of inflammatory disease are provided.

Abstract

La présente invention concerne d'une manière générale les composés qui présentent une activité inhibitrice de protéine kinase. Spécifiquement, la présente invention concerne des composés de formule (I) qui présentent une activité inhibitrice double vis-à-vis de l'ALK5 et de la MAP kinase P38A. La présente invention concerne également un ou des procédés pour la préparation de tels composés, des compositions pharmaceutiques contenant un ou une combinaison de ces composés, et des méthodes de traitement d'états associés à une activité excessive de l'un quelconque ou d'une combinaison du facteur de croissance transformant bêta (TGF-β) et de la protéine kinase p38 activée par le mitogène (MAPK) utilisant ces composés. Un aspect de la présente invention concerne des composés de formule (I) et un sel, un polymorphe, un solvate ou un stéréoisomère pharmaceutiquement acceptable de ceux-ci qui présentent une double activité inhibitrice contre ALK5 et P38 alpha: formule (I).
PCT/IB2019/050391 2018-01-18 2019-01-17 Inhibiteurs doubles de l'alk5 et de la map kinase p38α WO2019142128A1 (fr)

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US16/632,213 US20200171030A1 (en) 2018-01-18 2019-01-17 Dual inhibitors of alk5 and p38a map kinase

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IN201711025533 2018-01-18
IN201711025533 2018-01-18

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001030778A1 (fr) * 1999-10-27 2001-05-03 Novartis Ag Composes thiazole et imidazo [4,5-b] pyridine et leur utilisation pharmaceutique
WO2007067537A1 (fr) * 2005-12-07 2007-06-14 Osi Pharmaceuticals, Inc. Composés inhibant les pyrrolopyridine kinases
WO2009140128A2 (fr) * 2008-05-13 2009-11-19 Irm Llc Composés et compositions servant d'inhibiteurs de kinases
WO2014194127A1 (fr) * 2013-05-30 2014-12-04 Plexxikon Inc. Composés pour modulation de kinases, et indications correspondantes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001030778A1 (fr) * 1999-10-27 2001-05-03 Novartis Ag Composes thiazole et imidazo [4,5-b] pyridine et leur utilisation pharmaceutique
WO2007067537A1 (fr) * 2005-12-07 2007-06-14 Osi Pharmaceuticals, Inc. Composés inhibant les pyrrolopyridine kinases
WO2009140128A2 (fr) * 2008-05-13 2009-11-19 Irm Llc Composés et compositions servant d'inhibiteurs de kinases
WO2014194127A1 (fr) * 2013-05-30 2014-12-04 Plexxikon Inc. Composés pour modulation de kinases, et indications correspondantes

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